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EP3256469B1 - (r)-2-methyl-piperazine derivatives as cxcr3 receptor modulators - Google Patents

(r)-2-methyl-piperazine derivatives as cxcr3 receptor modulators Download PDF

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Publication number
EP3256469B1
EP3256469B1 EP16700487.8A EP16700487A EP3256469B1 EP 3256469 B1 EP3256469 B1 EP 3256469B1 EP 16700487 A EP16700487 A EP 16700487A EP 3256469 B1 EP3256469 B1 EP 3256469B1
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Prior art keywords
trifluoromethyl
methyl
triazol
thiazol
piperazin
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German (de)
English (en)
French (fr)
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EP3256469A1 (en
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Eva Caroff
Emmanuel Meyer
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Idorsia Pharmaceuticals Ltd
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Idorsia Pharmaceuticals Ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to (R) -2-methyl-piperazine derivatives of Formula (I), and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and especially their use as CXCR3 receptor modulators.
  • Chemokine receptors are a group of G-protein coupled receptors (GPCRs) that bind peptidic chemokine ligands with high affinity.
  • GPCRs G-protein coupled receptors
  • the predominant function of chemokine receptors is to guide leukocyte trafficking to lymphoid organs and tissues under resting conditions as well as during inflammation, but a role for certain chemokine receptors on non-hematopoietic cells and their progenitors has also been recognized.
  • the chemokine receptor CXCR3 is a G-protein coupled receptor binding to the inflammatory chemokines CXCL9 (initially called MIG, monokine induced by interferon- ⁇ [INF- ⁇ ]), CXCL10 (IP-10, INF- ⁇ -inducible protein 10), and CXCL11 (I-TAC, INF- ⁇ -inducible T cell ⁇ chemo-attractant).
  • CXCR3 is mainly expressed on activated T helper type 1 (Th1) lymphocytes, but is also present on natural killer cells, macrophages, dendritic cells and a subset of B lymphocytes.
  • the three CXCR3 ligands are expressed mainly under inflammatory conditions, expression in healthy tissue is very low.
  • Cells that can express CXCR3 ligands include diverse stromal cells such as endothelial cells, fibroblasts, epithelial cells, keratinocytes but also includes hematopoietic cells such as macrophages and monocytes.
  • CXCR3 and its ligands are involved in guiding receptor bearing cells to specific locations in the body, particularly to sites of inflammation, immune injury and immune dysfunction and is also associated with tissue damage, the induction of apoptosis, cell growth, and angiostasis.
  • CXCR3 and its ligands are upregulated and highly expressed in diverse pathological situations including autoimmune disorders, inflammation, infection, transplant rejection, fibrosis, neurodegeneration and cancer.
  • rheumatoid arthritis rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • IBD inflammatory bowel disease
  • type I diabetes mellitus Groom, J. R. & Luster, A. D. Immunol Cell Biol 2011, 89, 207 ; Groom, J. R.
  • mice deficient for one of the CXCR3 ligands or the use of antibodies blocking the function of either CXCR3 or one of its ligands further corroborate a role for the CXCR3 axis in immune pathology.
  • mice deficient for either CXCR3 or the CXCR3 ligand CXCL9 show reduced pathology in a model for lupus nephritis ( Menke, J. et al. J Am Soc Nephrol 2008, 19, 1177 ).
  • Inflammatory diseases that are associated with an elevated expression of the CXCR3 axis include chronic obstructive pulmonary disorder (COPD), asthma, sarcoidosis, atherosclerosis and myocarditis ( Groom, J. R. & Luster, A. D. Immunol Cell Biol 2011, 89, 207 ; Groom, J. R. & Luster, A. D. Exp Cell Res 2011, 317, 620 ).
  • COPD chronic obstructive pulmonary disorder
  • CXCR3 expression was found on all T cells within human atherosclerotic lesions.
  • CXCR3 ligands CXCL9, CXCL10 and CXCL11 were all found in endothelial and smooth muscle cells associated with those lesions, suggesting that they are involved in the recruitment and retention of CXCR3 positive cells, particularly activated T lymphocytes, observed within vascular wall lesions during atherogenesis ( Mach, F. et al. J Clin Invest 1999, 104, 1041 ).
  • CXCR3 deficient mice show a significant resistance to allograft rejection ( Hancock, W. W. et al. J Exp Med 2000, 192, 1515 ).
  • CXCR3 ligand plasma concentrations also positively correlate with diverse liver pathologies, including liver cirrhosis and fibrosis in humans ( Tacke, F., et al. Liver Int 2011, 31, 840 ).
  • CXCR3 axis In the central nervous system, blocking the CXCR3 axis may have beneficial effects and prevent neurodegeneration.
  • Increased expression of CXCL10 in the CNS has been demonstrated in ischemia, Alzheimer's disease, multiple sclerosis (MS), and human immunodeficiency virus (HIV)-encephalitis.
  • MS multiple sclerosis
  • HV human immunodeficiency virus
  • ex vivo experiments have shown that tissue derived from either CXCR3 or CXCL10 deficient mice, neuronal cell death was diminished after neurotoxic NMDA-treatment when compared to tissue derived from wild type mice ( van Weering, H. R. et al. Hippocampus 2011, 21, 220 ).
  • (R) -2-methyl-piperazine derivatives of Formula (I) are potent CXCR3 modulators with a surprisingly improved profile in a hERG Q-Patch assay indicating a reduced risk of QT prolongation.
  • These derivatives may be useful for the treatment of diseases that are mediated or sustained through the CXCR3 axis, including autoimmune disorders (e.g. rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, lupus nephritis, interstitial cystitis, celiac disease), inflammatory disorders (e.g.
  • asthma chronic myocarditis
  • myocarditis e.g. myocarditis
  • sarcoidosis e.g. transplantation rejection
  • fibrosis e.g. liver cirrhosis
  • neurodegeneration and conditions involving neuronal death e.g. Alzheimer's disease, Huntington's disease
  • cancer e.g. cancer, cardiovascular disease, diabetes, neurological disorders, neurological disorders, neurological disorders, neurological disorders, neurological disorders, and others.
  • the compounds of Formula (I) are (R) -configurated at the asymmetric carbon atom of the piperazine ring.
  • Definitions provided herein are intended to apply uniformly to the compounds of Formula (I) as defined in any one of embodiments 1) to 23), and, mutatis mutandis , throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
  • the compounds of Formula (I) as defined in any one of embodiments 1) to 23), may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of Formula (I) may thus be present as mixtures of stereoisomers or in stereoisomerically enriched form, preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • enriched for example when used in the context of enantiomers, is understood in the context of the present invention to mean especially that the respective enantiomer is present in a ratio (mutatis mutandis: purity) of at least 70:30, and notably of at least 90:10 (mutatis mutandis: purity of 70% / 90%) with respect to the respective other enantiomer.
  • the term refers to the respective essentially pure enantiomer.
  • essentially for example when used in a term such as "essentially pure” is understood in the context of the present invention to mean especially that the respective stereoisomer / composition / compound etc. consists in an amount of at least 90, especially of at least 95, and notably of at least 99 per cent by weight of the respective pure stereoisomer / composition / compound etc..
  • alkyl refers to a straight or branched saturated hydrocarbon chain containing one to four carbon atoms.
  • (C x-y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms.
  • a (C 1-4 )alkyl group contains from one to four carbon atoms.
  • Examples of (C 1-4 )alkyl groups are methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec .-butyl and tert.- butyl.
  • Examples of (C 1-2 )alkyl groups are methyl and ethyl.
  • R 1 represents "(C 1-4 )alkyl" the term means methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec .-butyl and tert .-butyl; preferably methyl, ethyl, n -propyl, iso -propyl and tert .-butyl; and more preferably ethyl and iso -propyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x-y )alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (C 1-4 )alkoxy group means a group of the formula (C 1-4 )alkyl-O- in which the term "(C 1-4 )alkyl" has the previously given significance.
  • Examples of (C 1-4 )alkoxy groups are methoxy, ethoxy, n -propoxy, iso -propoxy, n -butoxy, iso -butoxy, sec .-butoxy and tert .-butoxy.
  • Examples of (C 1-2 )alkoxy groups are methoxy and ethoxy.
  • R 2 represents "(C 1-4 )alkoxy" the term means methoxy, ethoxy, n -propoxy, iso -propoxy, n -butoxy, iso -butoxy, sec .-butoxy and tert .-butoxy and preferably ethoxy.
  • hydroxy-(C 1-4 )alkyl refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with hydroxy.
  • Examples of said groups are hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-prop-1-yl, 2-hydroxy-prop-1-yl, 3-hydroxy-prop-1-yl, 1-hydroxy-prop-2-yl, 2-hydroxy-prop-2-yl, 1-hydroxy-but-1-yl, 2-hydroxy-but-1-yl, 3-hydroxy-but-1-yl, 4-hydroxy-but-1-yl, 1-hydroxy-but-2-yl, 2-hydroxy-but-2-yl, 3-hydroxy-but-2-yl, 4-hydroxy-but-2-yl, 1-hydroxy-2-methyl-prop-1-yl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-2-methyl-prop-1-yl, and 2-hydroxy-1,1-dimethyl-eth-1-yl.
  • R 1 represents "hydroxy-(C 1-4 )alkyl"
  • the term means hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-prop-1-yl, 2-hydroxy-prop-1-yl, 3-hydroxy-prop-1-yl, 1-hydroxy-prop-2-yl, 2-hydroxy-prop-2-yl, 1-hydroxy-but-1-yl, 2-hydroxy-but-1-yl, 3-hydroxy-but-1-yl, 4-hydroxy-but-1-yl, 1-hydroxy-but-2-yl, 2-hydroxy-but-2-yl, 3-hydroxy-but-2-yl, 4-hydroxy-but-2-yl, 1-hydroxy-2-methyl-prop-1-yl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-2-methyl-prop-1-yl, and 2-hydroxy-1,1-dimethyl-eth-1-yl.
  • Preferred are hydroxy-methyl, 1-hydroxy-ethyl and 2-hydroxy-prop-2-yl and more preferred is 1-hydroxy-ethyl.
  • (C xa-ya )alkoxy-(C x-y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms wherein one hydrogen atom has been replaced with (C xa-ya )alkoxy as defined before containing xa to ya carbon atoms.
  • a "(C 1-2 )alkoxy-(C 1-2 )alkyl group” refers to an (C 1-2 )alkyl group as defined before containing one or two carbon atoms wherein one hydrogen atom has been replaced with (C 1-2 )alkoxy as defined before containing one or two carbon atoms.
  • Examples of (C 1-2 )alkoxy-(C 1-2 )alkyl groups are methoxy-methyl, 1-methoxy-ethyl, 2-methoxy-ethyl, ethoxy-methyl, 1-ethoxy-ethyl and 2-ethoxy-ethyl.
  • R 1 represents "(C 1-2 )alkoxy-(C 1-2 )alkyl" the term means methoxy-methyl, 1-methoxy-ethyl, 2-methoxy-ethyl, ethoxy-methyl, 1-ethoxy-ethyl and 2-ethoxy-ethyl and preferably methoxy-methyl.
  • fluoroalkyl refers to an alkyl group as defined before containing one or two carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (C 1-2 )fluoroalkyl group contains one or two carbon atoms in which one to five hydrogen atoms have been replaced with fluorine.
  • Representative examples of (C 1-2 )fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.
  • R 2 represents "(C 1-2 )fluoroalkyl" the term means preferably fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl and more preferably trifluoromethyl.
  • cycloalkyl refers to a saturated carbocyclic ring containing three to six carbon atoms.
  • (C x-y )cycloalkyl refers to a cycloalkyl group as defined before containing x to y carbon atoms.
  • a (C 3-6 )cycloalkyl group contains from three to six carbon atoms.
  • Examples of (C 3-6 )cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 2 represents "(C 3-6 )cycloalkyl” the term means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and preferably cyclopropyl.
  • cycloalkoxy refers to a cycloalkyl-O- group wherein the cycloalkyl group is as defined before.
  • (C x-y )cycloalkoxy refers to a cycloalkoxy group as defined before containing x to y carbon atoms.
  • a (C 3-6 )cycloalkoxy group means a group of the formula (C 3-6 )cycloalkyl-O- in which the term "(C 3-6 )cycloalkyl" has the previously given significance.
  • Examples of (C 3-6 )cycloalkoxy groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • R 2 represents "(C 3-6 )cycloalkoxy" the term means cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy and preferably cyclobutyloxy.
  • any reference to a compound of Formula (I) as defined in any one of embodiments 1) to 23) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • pharmaceutically acceptable salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of Formula (I), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • the term “about” (or alternatively “around”) placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” (or alternatively “around”) placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
  • room temperature refers to a temperature of about 25°C.
  • the compounds of formula (I) as defined in any one of embodiments 1) to 23) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral (including topical application or inhalation) administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins ]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of Formula (I) as defined in any one of embodiments 1) to 23).
  • the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
  • Another aspect of the invention concerns a method for the prevention or the treatment of a disease or disorder as mentioned below in a patient comprising the administration to said patient of a pharmaceutically active amount of a compound of Formula (I) as defined in any one of embodiments 1) to 23) or a pharmaceutically acceptable salt thereof.
  • the compounds according to Formula (I) as defined in any one of embodiments 1) to 23), or pharmaceutically acceptable salts thereof, are useful for the prevention or treatment of disorders relating to a dysfunction of the CXCR3 receptor or dysfunction of ligands signalling through CXCR3.
  • disorders relating to a dysfunction of the CXCR3 receptor or its ligands are diseases or disorders where a modulator of a human CXCR3 receptor is required.
  • the above mentioned disorders may in particular be defined as comprising autoimmune disorders, inflammatory diseases, infectious diseases, transplant rejection, fibrosis, neurodegenerative disorders and cancer.
  • Autoimmune disorders may be defined as comprising rheumatoid arthritis (RA); multiple sclerosis (MS); inflammatory bowel disease (IBD; comprising Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE); psoriasis; psoriatic arthritis; lupus nephritis; interstitial cystitis; celiac disease; antiphospholipid syndrome; thyroiditis such as Hashimoto's thyroiditis; lymphocytic thyroiditis; myasthenia gravis; type I diabetes; uveitis; episcleritis; scleritis; Kawasaki's disease, uveo-retinitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; and post-infectious
  • Inflammatory diseases may be defined as comprising asthma; COPD; atherosclerosis; myocarditis; dry eye syndrome (comprising Sjögren's dry eye syndrome); myopathies (comprising inflammatory myopathies); sarcoidosis; pulmonary arterial hypertension, especially associated with sarcoidosis; and obesity.
  • Infectious diseases may be defined as comprising diseases mediated by various infectious agents and complications resulting threrefrom; such as malaria, cerebral malaria, leprosy, tuberculosis, influenza, toxoplasma gondii, dengue, hepatitis B and C, herpes simplex, leishmania, chlamydia trachomatis, lyme disease, west nile virus.
  • diseases mediated by various infectious agents and complications resulting threrefrom such as malaria, cerebral malaria, leprosy, tuberculosis, influenza, toxoplasma gondii, dengue, hepatitis B and C, herpes simplex, leishmania, chlamydia trachomatis, lyme disease, west nile virus.
  • Transplant rejection may be defined as comprising rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host diseases; and chronic allograft vasculopathy.
  • Fibrosis may be defined as comprising liver cirrhosis (comprising primary biliary cirrhosis (PBC) and autoimmune hepatitis), idiopathic pulmonary fibrosis, renal fibrosis, endomyocardial fibrosis, systemic sclerosis, and arthrofibrosis.
  • liver cirrhosis comprising primary biliary cirrhosis (PBC) and autoimmune hepatitis
  • PBC primary biliary cirrhosis
  • hepatitis idiopathic pulmonary fibrosis
  • renal fibrosis idiopathic pulmonary fibrosis
  • endomyocardial fibrosis endomyocardial fibrosis
  • systemic sclerosis and arthrofibrosis.
  • Neurodegenerative disorders may be defined as comprising neurodegeneration and conditions involving neuronal death such as multiple sclerosis (including relapsing remitting multiple sclerosis and progressive multiple sclerosis), Alzheimer's disease, Parkinson's disease, Huntington's chorea, HIV associated dementia, prion mediated neurodegeneration, epilepsy, stroke, cerebral ischemia, cerebral palsy, neuromyelitis optica, clinically isolated syndrome, Alpers' disease, amyotrophic lateral sclerosis (ALS), senile dementia, dementia with Lewy bodies, Rett syndrome, spinal cord trauma, traumatic brain injury, trigeminal neuralgia, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, narcolepsy, glossopharyngeal neuralgia, mild cognitive decline, cognitive decline, spinal muscular atrophy, and cerebral malaria.
  • multiple sclerosis including relapsing remitting multiple sclerosis and progressive multiple sclerosis
  • Alzheimer's disease Parkinson's disease,
  • Cancer may be defined as comprising all sorts of cancers such as large intestine cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophagal cancer, stomach cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, urinary bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreas cancer, brain tumor, blood tumor, basophil adenoma, prolactinoma, hyperprolactinemia, adenomas, endometrial cancer, colon cancer; chronic lymphocytic leukemia (CLL); and especially the metastatic spread of those cancers.
  • cancers such as large intestine cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophagal cancer, stomach cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, urinary bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer,
  • compounds of Formula (I) according to any one of embodiments 1) to 23), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of diseases selected from one, several or all of the following groups of diseases and disorders:
  • a further aspect of the invention is a process for the preparation of compounds of Formula (I).
  • Compounds according to Formula (I) of the present invention can be prepared from commercially available or well known starting materials according to the methods described in the experimental part; by analogous methods; or according to the general sequence of reactions outlined below, wherein R 1 and R 2 are as defined for Formula (I). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section.
  • the generic groups R 1 and R 2 might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG).
  • the use of protecting groups is well known in the art (see for example " Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999 ). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place.
  • the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known per se.
  • Compounds of Formula (I) can be prepared starting from intermediate (1), which is saponified under standard conditions (e.g. aq. NaOH in MeOH) to give compounds of structure (2) (Scheme 1).
  • the carboxylic acid group in the compound of structure (2) is converted to the corresponding bromine (3) using (diacetoxyiodo)benzene and LiBr in THF at RT.
  • Suzuki coupling can be performed using a coupling partner of structure (4), wherein R represents hydrogen or (C 1-4 )alkyl, using standard conditions for a Suzuki reaction, like using a suitable base such as aq.
  • the Boc protecting group of the obtained intermediate (5) can be subsequently cleaved under acidic conditions, preferably using HCI in a suitable solvent such as dioxane and at a temperature about RT to give the compound of structure (6).
  • Compounds of Formula (I) can be obtained in a final step by an amide coupling with a carboxylic acid derivative (7) using standard peptide coupling methods such as HATU, in presence of a suitable base such as DIPEA or NEt 3 and in a suitable solvent such as DCM or DMF, preferably at a temperature about RT.
  • a suitable base such as DIPEA or NEt 3
  • a suitable solvent such as DCM or DMF
  • a triazole of structure (9) can be alkylated using an acetic acid derivative of formula X-CH 2 -COO(PG), wherein X is a leaving group such as bromine and PG is a protecting group suitable for an acid function (e.g. benzyl), in presence of a base such as Cs 2 CO 3 , in a suitable solvent such as MeCN, and at a temperature around RT.
  • X is a leaving group such as bromine
  • PG is a protecting group suitable for an acid function (e.g. benzyl)
  • a base such as Cs 2 CO 3
  • MeCN a suitable solvent
  • the compounds of structure (4) are either commercially available or can be prepared in analogy to methods known to one skilled in the art such as the reaction of the respective 5-bromo-pyrimidine derivative with triisopropyl borate and n-BuLi in THF and toluene at a temperature around -78°C.
  • Compounds of Formula (I) may be obtained from other compounds of Formula (I) or their analogues by interconversion of a substituent in R 1 -position to another substituent R 1 .
  • an analogue of Formula (I) wherein R 1 represents bromine may be transferred to a compound of Formula (I) wherein R 1 represents (C 2-4 )alkyl by (i) Suzuki reaction using the respective (C 2-4 )alkenylboronic acid ester derivative (e.g. isopropenyboronic acid pinacol ester) in the presence of a palladium catalyst such as Pd(PPh 3 ) 2 Cl 2 and (ii) hydrogenation using for instance hydrogen in the presence of Pd/C in a solvent such as MeOH.
  • a palladium catalyst such as Pd(PPh 3 ) 2 Cl 2
  • hydrogenation for instance hydrogen in the presence of Pd/C in a solvent such as MeOH.
  • a compound of Formula (I) wherein R 1 represents -C(O)NH 2 may be prepared by hydrolysis of the respective nitrile using conc. H 2 SO 4 in a solvent such as DCM. Further, a compound of Formula (I) wherein R 1 represents hydroxy-(C 1-4 )alkyl may be obtained from the respective compound wherein R 1 represents methoxy-(C 1-4 )alkyl by demethylation using BBr 3 in a solvent such as DCM or from the respective ketone wherein R 1 represents -C(O)-(C 1-3 )alkyl by reduction with NaBH 4 .
  • the enantiomers can be separated using methods known to one skilled in the art: e.g . by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Daicel ChiralPak IC (5 ⁇ m) column.
  • a chiral stationary phase such as a Daicel ChiralPak IC (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH or i PrOH, in presence or absence of an amine such as NEt 3 or DEA) and eluent B (hexane or MeCN), at a flow rate of 0.8 to 16 mL/min.
  • a ChiralPak IB column (5 ⁇ m, 30x250mm) was used.
  • the elution solvent was Hep/EtOH 60/40, run for 9min and at a flow rate of 40mL/min.
  • a (R,R) Whelk-01 column (10 ⁇ m, 50x250mm) was used.
  • the elution solvent was Hep/EtOH 70/30, run for 16.3min and at a flow rate of 100mL/min.
  • a ChiralPak IB column (5 ⁇ m, 30x250mm) was used.
  • the elution solvent was Hep/EtOH 50/50, run for 8min and at a flow rate of 34mL/min.
  • a ChiralPak IB column (5 ⁇ m, 20x250mm) was used.
  • the elution solvent was Hep/EtOH 50/50, 0.1% DEA, run for 18.7min and at a flow rate of 16mL/min.
  • a ChiralPak IB column (5 ⁇ m, 30x250mm) was used.
  • the elution solvent was Hep/EtOH 70/30, run for 11.8min and at a flow rate of 34mL/min.
  • a ChiralPak OZ-H column (5 ⁇ m, 20x250mm) was used.
  • the elution solvent was Hep/EtOH 50/50, 0.1% DEA, run for 11min and at a flow rate of 19mL/min.
  • Example 1 1- ⁇ (R)-4-[4-(2-Ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-methyl-piperazin-1-yl ⁇ -2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone
  • the residue was purified by CC (Biotage, SNAP 100g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in %B: 15 for 4CV, 15 to 100 over 4CV, 100 for 1CV) to afford 3.89g as first eluting fraction (mixture of two triazole regioisomers) and 309mg as second eluting fraction ((3-ethyl-[1,2,4]triazol-4-yl)-acetic acid benzyl ester).
  • the mixture of regioisomers was purified by preparative chiral HPLC (I).
  • Second eluting fraction (3-ethyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester: 2.08g yellow solid.
  • LC-MS (A): t R 0.71min; [M+H] + : 246.2. Roesy signal seen between CH at 8.08 ppm (triazole) and CH 2 CO 2 at 4.96ppm.
  • This compound was prepared using a method analogous to that of Example 2, step 2.1, 3-(methoxymethyl)-1H-1,2,4-triazol replacing 3-ethyl-1H-1,2,4-triazole.
  • the crude was purified by two CC (1. Biotage, SNAP 10g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in %B: 5 for 7CV, 5 to 15 over 3CV, 15 for 3CV. 2.
  • Second eluting fraction (5-isopropyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester.
  • LC-MS (A): t R 0.76min; [M+H] + : 260.2. Roesy signal seen between CH 2 at 4.96ppm and CH (isopropyl) at 2.97ppm.
  • step 7.1 the mixture of regioisomers from step 7.1 was used to give a mixture of (3-isopropyl-[1,2,4]triazol-1-yl)-acetic acid and (5-isopropyl-[1,2,4]triazol-1-yl)-acetic acid.
  • This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 5.2 replacing intermediate 1.7 and intermediate 3.2 replacing intermediate 2.2.
  • Second eluting fraction (3-propyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester.
  • LC-MS (A): t R 0.76min; [M+H] + : 260.1. Roesy signal seen between CH 2 CO 2 at 4.96ppm and CH (triazole) at 8.08ppm.
  • Example 12 2-[3-(1-Hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1- ⁇ (R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl ⁇ -ethanone
  • This compound was prepared using a method analogous to that of Example 2, step 2.1, 1-(1H-1,2,4-triazol-5-yl)ethanone replacing 3-ethyl-1H-1,2,4-triazole.
  • the crude was purified by CC (Biotage, SNAP 10g cartridge, solvent A: Hep; solvent B: EA; gradient in %B: 30 for 4CV, 30 to 70 over 4CV, 70 for 2CV, 70 to 100 over 2CV, 100 for 2CV) to give the desired triazole regioisomer as second fraction.
  • LC-MS (A): t R 0.7min; [M+H] + : 260.1. Roesy signal seen between CH (triazole) at 8.28ppm and CH 2 at 5.1ppm.
  • Example 13 2-[3-(1-Hydroxy-1-methyl-ethyl)-[1,2,4]triazol-1-yl]-1- ⁇ (R)-2-methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl ⁇ -ethanone
  • This compound was prepared using a method analogous to that of Example 1, step 1.6, 2-(cyclobutoxy)pyrimidine-5-boronic replacing 2-ethoxypyrimidine-5-boronic acid.
  • the crude was purified by Prep LC-MS (II) instead of CC.
  • LC-MS (A): t R 1.08min; [M+H] + : 500.1.
  • This compound was prepared using a method analogous to that of Example 2, step 2.3, intermediate 14.2 replacing intermediate 1.7 and the regioisomeric mixture in step 7.2 replacing intermediate 2.2.
  • the crude was purified by CC (DCM/MeOH 97:3) followed by Prep LC-MS (I) and Preparative chiral HPLC (IV).
  • This compound was prepared using a method analogous to that of Example 2, step 2.1, 3-methyl-1H-1,2,4-triazole replacing 3-ethyl-1H-1,2,4-triazole.
  • the mixture of regioisomers was purified by preparative chiral HPLC (V). First eluting fraction: (5-methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester.
  • LC-MS (A): t R 0.68min; [M+H] + : 232.16.
  • FLIPR assay The bioactivity of compounds is tested in a fluorometric imaging plate reader (FLIPR: Molecular Devices) using engineered CHO-K1 cells expressing the human CXCR3A (GenBank: AY242128) coupled to a G protein (Galpha(16)). Cells are plated the day prior to bioassay in F12 medium supplemented with 10% FBS and G418 and hygromycin antibiotics to maintain recombinant selection.
  • FLIPR Fluorometric imaging plate reader
  • test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in dilution buffer to concentrations required for inhibition dose response curves. After a 10 minute incubation period at 37°C, 10 microliters of each compound dilution are transferred from a compound plate to the plate containing the recombinant cells in the FLIPR instrument according to the manufacturer's instructions. Following basal readings, 10 microliter CXCL10 agonist at a concentration of 20 nM (from Peprotech) is added, again using the FLIPR instrument. Changes in fluorescence are monitored before and after addition of the test compounds. Emission peak values above base level after CXCL10 addition are exported after base line subtraction.
  • RIA Receptor internalization assay: Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in PBS containing 0,5% BSA to concentrations required for inhibition dose response curves. Diluted compounds are then mixed with an equal volume of CXCL10 (Peprotech) diluted in PBS. Anticoagulated venous human whole blood is added to the mixture, which is then incubated in a CO 2 incubator at 37°C to allow for ligand mediated receptor internalization (final CXCL10 concentration is 9 nM). After 30 min, the blood is mixed with fluorescently labeled CXCR3 and CD4 specific antibodies (Becton Dickinson) and incubated on ice for 10 minutes.
  • IC 50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where IC 50 values have been determined several times for the same compound, mean values are given.
  • Cells are grown in culture flasks at 37°C in 5% CO 2 , in culture medium (Ham's F-12 Nutrient Mixture, Invitrogen 21765-029) supplemented with 9% (v/v) fetal calf serum, 0.9% Penicillin/Streptomycin (10,000 U/mL, Invitrogen 15140148), 100 ⁇ g/mL Hygromycin B (Invitrogen 10687010).
  • culture medium Ham's F-12 Nutrient Mixture, Invitrogen 21765-029
  • Penicillin/Streptomycin 10,000 U/mL, Invitrogen 15140148
  • 100 ⁇ g/mL Hygromycin B Hygromycin B
  • Currents are low-pass filtered using the internal Bessel filter of the QPatch robot with a cutoff frequency of 2 kHz and are digitized at 10 kHz.
  • K + tail currents are produced from a holding voltage of -80 mV by a 500-ms depolarization to +20 mV followed by a 500-ms repolarization to -40 mV; tail current amplitudes are measured at the end of the repolarization to -40 mV.
  • the pulse pattern is repeated every 10 sec during the experiment, baseline K + current is measured after 3 min in extracellular solution, test-solution containing compound is then applied, and K + current in presence of compound is measured 3 minutes after application to the cells.
  • the respective test-solution is prepared by (1) dissolving the test-compound in pure DMSO, (2) diluting this DMSO solution in extracellular solution, and (3) adding further DMSO, such that the final test-solution has a concentration of either 300 nM or 3000 nM of the test-compound and contains 0.3 %v/v DMSO.
  • Compound effects are quantified as % block by dividing the current in presence of compound by the baseline current; two or three experiments are performed for each compound and the final value represents the mean of the results of each experiment.

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US20180009800A1 (en) 2018-01-11
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US10047080B2 (en) 2018-08-14
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CA2972954C (en) 2023-08-29
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